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We sought to determine whether improved cycling performance following ‘Live High-Train Low’ (LHTL) occurs if increases in haemoglobin mass (Hb mass ) are prevented via periodic phlebotomy during hypoxic exposure. Eleven, highly trained, female cyclists completed 26 nights of simulated LHTL (16 h day −1 , 3000 m). Hb mass was determined in quadruplicate before LHTL and in duplicate weekly thereafter. After 14 nights, cyclists were pair-matched, based on their Hb mass response (ΔHb mass ) from baseline, to form a response group (Response, n  = 5) in which Hb mass was free to adapt, and a Clamp group (Clamp, n  = 6) in which ΔHb mass was negated via weekly phlebotomy. All cyclists were blinded to the blood volume removed. Cycling performance was assessed in duplicate before and after LHTL using a maximal 4-min effort (MMP 4min ) followed by a ride time to exhaustion test at peak power output ( T lim ). VO 2peak was established during the MMP 4min . Following LHTL, Hb mass increased in Response (mean ± SD, 5.5 ± 2.9%). Due to repeated phlebotomy, there was no ΔHb mass in Clamp (−0.4 ± 0.6%). VO 2peak increased in Response (3.5 ± 2.3%) but not in Clamp (0.3 ± 2.6%). MMP 4min improved in both the groups (Response 4.5 ± 1.1%, Clamp 3.6 ± 1.4%) and was not different between groups ( p  = 0.58). T lim increased only in Response, with Clamp substantially worse than Response (−37.6%; 90% CL −58.9 to −5.0, p  = 0.07). Our novel findings, showing an ~4% increase in MMP 4min despite blocking an ~5% increase in Hb mass , suggest that accelerated erythropoiesis is not the sole mechanism by which LHTL improves performance. However, increases in Hb mass appear to influence the aerobic contribution to high-intensity exercise which may be important for subsequent high-intensity efforts.

Accurate estimates of the BOLD hemodynamic response function (HRF) are crucial for the interpretation and analysis of event-related functional MRI data. To date, however, there have been no comprehensive measurements of the HRF in white matter (WM) despite increasing evidence that BOLD signals in WM change after a stimulus. We performed an event-related cognitive task (Stroop color-word interference) to measure the HRF in selected human WM pathways. The task was chosen in order to produce robust, distributed centers of activity throughout the cortex. To measure the HRF in WM, fiber tracts were reconstructed between each pair of activated cortical areas. We observed clear task-specific HRFs with reduced magnitudes, delayed onsets and prolonged initial dips in WM tracts compared with activated grey matter, thus calling for significant changes to current standard models for accurately characterizing the HRFs in WM and for modifications of standard methods of analysis of functional imaging data. The hemodynamic response function (HRF) describes how changes in brain activity manifest as a transient signal (BOLD) that is detected by fMRI imaging. Here, the authors show that the HRF in white matter shows reduced magnitudes, delayed onsets, and prolonged initial dips compared to the grey matter HRF.

There is conflicting evidence whether hypoxia improves running economy (RE), maximal O 2 uptake ( V ˙ O 2   max ), haemoglobin mass (Hb mass) and performance, and what total accumulated dose is necessary for effective adaptation. The aim of this study was to determine the effect of an extended hypoxic exposure on these physiological and performance measures. Nine elite middle distance runners were randomly assigned to a live high–train low simulated altitude group (ALT) and spent 46 ± 8 nights (mean ± S.D.) at 2860 ± 41 m. A matched control group (CON, n = 9) lived and trained near sea level (∼600 m). ALT decreased submaximal V ˙ O 2 (L min −1) (−3.2%, 90% confidence intervals, −1.0% to −5.2%, p = 0.02), increased Hb mass (4.9%, 2.3–7.6%, p = 0.01), decreased submaximal heart rate (−3.1%, −1.8% to −4.4%, p = 0.00) and had a trivial increase in V ˙ O 2   max (1.5%, −1.6 to 4.8; p = 0.41) compared with CON. There was a trivial correlation between change in Hb mass and change in V ˙ O 2   max ( r = 0.04, p = 0.93). Hypoxic exposure of ∼400 h was sufficient to improve Hb mass, a response not observed with shorter exposures. Although total O 2 carrying capacity was improved, the mechanism(s) to explain the lack of proportionate increase in V ˙ O 2   max were not identified.

When different species experience similar selection pressures, the probability of evolving similar adaptive solutions may be influenced by legacies of evolutionary history, such as lineage-specific changes in genetic background. Here we test for adaptive convergence in hemoglobin (Hb) function among high-altitude passerine birds that are native to the Qinghai-Tibet Plateau, and we examine whether convergent increases in Hb–O₂ affinity have a similar molecular basis in different species. We documented that high-altitude parid and aegithalid species from the Qinghai-Tibet Plateau have evolved derived increases in Hb–O₂ affinity in comparison with their closest lowland relatives in East Asia. However, convergent increases in Hb–O₂ affinity and convergence in underlying functional mechanisms were seldom attributable to the same amino acid substitutions in different species. Using ancestral protein resurrection and site-directed mutagenesis, we experimentally confirmed two cases in which parallel substitutions contributed to convergent increases in Hb–O₂ affinity in codistributed high-altitude species. In one case involving the ground tit (Parus humilis) and gray-crested tit (Lophophanes dichrous), parallel amino acid replacements with affinity-enhancing effects were attributable to nonsynonymous substitutions at a CpG dinucleotide, suggesting a possible role for mutation bias in promoting recurrent changes at the same site. Overall, most altitude-related changes in Hb function were caused by divergent amino acid substitutions, and a select few were caused by parallel substitutions that produced similar phenotypic effects on the divergent genetic backgrounds of different species.

Sickle cell disease is caused by an alteration in a single DNA base, but its clinical manifestations are influenced by other genes and behavioral and environmental factors. Recent findings may indicate an acceleration in the discovery of interventions that alter the disease course. Sickle cell disease is an increasing global health problem. Estimates suggest that every year approximately 300,000 infants are born with sickle cell anemia, which is defined as homozygosity for the sickle hemoglobin (HbS) gene (i.e., for a missense mutation [Glu6Val, rs334] in the β-globin gene [ HBB ]) and that this number could rise to 400,000 by 2050. 1 Although early diagnosis, penicillin prophylaxis, blood transfusion, transcranial Doppler imaging, hydroxyurea, and hematopoietic stem-cell transplantation can dramatically improve survival and quality of life for patients with sickle cell disease, our understanding of the role of genetic and nongenetic factors in explaining the . . .

Neural mechanisms that mediate dynamic social interactions remain understudied despite their evolutionary significance. The interactive brain hypothesis proposes that interactive social cues are processed by dedicated brain substrates and provides a general theoretical framework for investigating the underlying neural mechanisms of social interaction. We test the specific case of this hypothesis proposing that canonical language areas are upregulated and dynamically coupled across brains during social interactions based on talking and listening. Functional near-infrared spectroscopy (fNIRS) was employed to acquire simultaneous deoxyhemoglobin (deOxyHb) signals of the brain on partners who alternated between speaking and listening while doing an Object Naming & Description task with and without interaction in a natural setting. Comparison of interactive and non-interactive conditions confirmed an increase in neural activity associated with Wernicke's area including the superior temporal gyrus (STG) during interaction (P = 0.04). However, the hypothesis was not supported for Broca's area. Cross-brain coherence determined by wavelet analyses of signals originating from the STG and the subcentral area was greater during interaction than non-interaction (P < 0.01). In support of the interactive brain hypothesis these findings suggest a dynamically coupled cross-brain neural mechanism dedicated to pathways that share interpersonal information.

Leghemoglobins transport and deliver O₂ to the symbiosomes inside legume nodules and are essential for nitrogen fixation. However, the roles of other hemoglobins (Hbs) in the rhizobia–legume symbiosis are unclear. Several Lotus japonicus mutants affecting LjGlb1-1, a non-symbiotic class 1 Hb, have been used to study the function of this protein in symbiosis. Two TILLING alleles with single amino acid substitutions (A102V and E127K) and a LORE1 null allele with a retrotransposon insertion in the 5′-untranslated region (96642) were selected for phenotyping nodulation. Plants of all three mutant lines showed a decrease in long infection threads and nodules, and an increase in incipient infection threads. About 4 h after inoculation, the roots of mutant plants exhibited a greater transient accumulation of nitric oxide (NO) than did the wild-type roots; nevertheless, in vitro NO dioxygenase activities of the wild-type, A102V, and E127K proteins were similar, suggesting that the mutated proteins are not fully functional in vivo. The expression of LjGlb1-1, but not of the other class 1 Hb of L. japonicus (LjGlb1-2), was affected during infection of wild-type roots, further supporting a specific role for LjGlb1-1. In conclusion, the LjGlb1-1 mutants reveal that this protein is required during rhizobial infection and regulates NO levels.

▪ Abstract  Blood flow in the microcirculation is regulated by physiological oxygen (O 2 ) gradients that are coupled to vasoconstriction or vasodilation, the domain of nitric oxide (NO) bioactivity. The mechanism by which the O 2 content of blood elicits NO signaling to regulate blood flow, however, is a major unanswered question in vascular biology. While the hemoglobin in red blood cells (RBCs) would appear to be an ideal sensor, conventional wisdom about its chemistry with NO poses a problem for understanding how it could elicit vasodilation. Experiments from several laboratories have, nevertheless, very recently established that RBCs provide a novel NO vasodilator activity in which hemoglobin acts as an O 2 sensor and O 2 -responsive NO signal transducer, thereby regulating both peripheral and pulmonary vascular tone. This article reviews these studies, together with biochemical studies, that illuminate the complexity and adaptive responsiveness of NO reactions with hemoglobin. Evidence for the pivotal role of S-nitroso (SNO) hemoglobin in mediating this response is discussed. Collectively, the reviewed work sets the stage for a new understanding of RBC-derived relaxing activity in auto-regulation of blood flow and O 2 delivery and of RBC dysfunction in disorders characterized by tissue O 2 deficits, such as sickle cell disease, sepsis, diabetes, and heart failure.

Sickle cell anemia (SCA) is an inherited blood disorder that causes painful crises due to vaso-occlusion of small blood vessels. The primary cause of the clinical phenotype of SCA is the intracellular polymerization of sickle hemoglobin resulting in sickling of red blood cells (RBCs) in deoxygenated conditions. In this review, we discuss the biomechanical and biorheological characteristics of sickle RBCs and sickle blood as well as their implications toward a better understanding of the pathophysiology and pathogenesis of SCA. Additionally, we highlight the adhesive heterogeneity of RBCs in SCA and their specific contribution to vaso-occlusive crisis.

Truncated hemoglobins constitute a large family, present in bacteria, in archaea and in eukaryotes. However, a majority of physiological functions of these proteins remains to be elucidated. Identification and characterization of a novel role of truncated hemoglobins in the model alga provides a framework for a more complete understanding of their biological functions. Here, we use quantitative RT-PCR to show that three truncated hemoglobins of Chlamydomonas reinhardtii, THB1, THB2 and THB12, are induced under conditions of depleted sulfur (S) supply. THB1 underexpression results in the decrease in cell size, as well in levels of proteins, chlorophylls and mRNA of several S-responsive genes under S starvation. We provide evidence that knock-down of THB1 enhances NO production under S deprivation. In S-deprived cells, a subset of S limitation-responsive genes is controlled by NO in THB1-dependent pathway. Moreover, we demonstrate that deficiency for S represses the nitrate reduction and that THB1 is involved in this control. Thus, our data support the idea that in S-deprived cells THB1 plays a dual role in NO detoxification and in coordinating sulfate limitation with nitrate assimilation. This study uncovers a new function for the Chlamydomonas reinhardtii THB1 in the control of proper response to S deprivation.